RU2334513C2 - Pharmaceutical compositions including valsartan and inhibitors of neutral endopeptitas (nep) - Google Patents

Abstract

FIELD: medicine, pharmacology.

SUBSTANCE: invention relates to pharmaceutical combination including: i) antagonist AT-1 valsartan or its pharmaceutically acceptable salt in single day dose from approximately 20 mg to approximately 320 mg, and (ii) inhibitor NEP representing ethyl ether of N-(3-carboxy-1-oxopropyl)-(4S)-n-phenylphenylmethyl)-4-amino-2R-methylbutane acid or N-(3-carboxy-1-oxopropyl)-(4S)-n-phenylphenylmethyl)-4-amino-2R-methylbutanic acid or their pharmaceutically acceptable salt in a single day dose from approximately 20 mg to approximately 800 mg. In addition, invention relates to kit for treatment including said combination.

EFFECT: synergetic effect of hypertensia treatment when using said combination.

5 cl, 6 tbl, 7 ex

Description

Angiotensin II interacts with specific receptors on the surface of the target cell. It has been possible to identify subtypes of receptors called, for example, AT 1 and AT 2 receptors. Recently, great efforts have been made to identify substances that bind to AT 1 receptor. Such active ingredients are often called angiotensin II antagonists. Due to inhibition of the AT 1 receptor, such antagonists can be used, for example, as antihypertensive agents or, among other indications, for the treatment of congestive heart failure. Therefore, it is understood that angiotensin II antagonists are those active ingredients that bind to the AT 1 receptor subtype.

Inhibitors of the renin-angiotensin system are well-known drugs that lower blood pressure and have beneficial effects in hypertension and congestive heart failure, as described, for example, N. Eng. J.Med. 316, 23 (1987), 1429-1435. A large number of peptide and non-peptide inhibitors of the renin-angiotensin system are known, the most widely studied are angiotensin-converting enzyme (ACE) inhibitors, which include captopril, enalapril, lisinopril, benazepril, and spirapril. Although the main type of action of ACE inhibitors includes preventing the formation of Ang II vasoconstrictive peptide, Hypertension 16, 4 (1990), 363-370 reports that ACE cleaves various peptide substrates, including vascular peptides bradykinin and substance P. Prevention of degradation has been demonstrated. bradykinin as ACE inhibitors and reported in Circ. Res., 66, 1 (1990), 242-248, that the activity of ACE inhibitors in some conditions is mediated more by a decrease in bradykinin levels than by inhibition of Ang II formation. Therefore, it cannot be assumed that the effect of the ACE inhibitor is explained only by preventing the formation of angiotensin and subsequent inhibition of the renin-angiotensin system.

Neutral endopeptidase (EC 3.4.24.11; enkephalinase; atriopeptidase; NEP) is a zinc-containing metalloprotease that cleaves various peptide substrates on the amino-terminal side of aromatic amino acids. See Biochem. J., 241, (1987), 237-247. Substrates of this enzyme include, but are not limited to, atrial natriuretic factors (ANF, also known as ANP), cerebral natriuretic peptide (BNP), methionine and leucine enkephalin, bradykinin, neurokinin A and substance P.

ANPs are a family of vasodilating, diuretic and antihypertensive peptides that have been the subject of many recent literature reports, such as Annu. Rev. Pharm. Tox., 29, (1989), 23-54. One form, ANF 99-126, is a peptide hormone circulating in the circulatory system that is released from the heart under conditions of cardiac expansion. The function of ANF is to maintain salt and water homeostasis, as well as the regulation of blood pressure. ANF is rapidly deactivated in the circulatory system in at least two ways: receptor-mediated clearance reported in Am. J. Physiol., 256 (1989), R469-R475, and enzymatic deactivation via NEP, reported in Biochem. J., 243 (1987), 183-187. It has been previously demonstrated that NEP inhibitors potentiate antihypertensive, diuretic, natriuretic and plasma ANF responses in experimental animals to pharmacological injection of ANF. Potentiation of ANF by two specific NEP inhibitors has been reported by Sybertz et al., J. Pharmacol. Exp. Ther. 250, 2 (1989), 624-631 and Hypertension, 15, 2 (1990), 152-161, while the potentiation of ANF is generally disclosed in US Pat. No. 4,749,688. In US Pat. No. 4,740,499, Olins discloses the use of thiorphan and kelatorfan for potentiation of atrial peptides. . Moreover, NEP inhibitors lower blood pressure and exhibit ANF-like effects, such as diuresis, and increased secretion of cyclic guanosine-3 ', 5'-monophosphate (cGMP) in some forms of experimental hypertension. The antihypertensive effect of NEP inhibitors is mediated through ANF, because antibodies to ANF will neutralize the decrease in blood pressure.

Prolonged and uncontrolled hypertensive vascular disease eventually leads to various pathological changes in target organs, such as the heart and kidneys. Stable hypertension can also lead to an increase in paralysis. Therefore, there is a great need to evaluate the effectiveness of antihypertensive therapy, to study the cardiovascular endpoints of the lesion after lowering blood pressure, in order to gain an additional idea of the benefits of combination therapy.

The nature of hypertensive vascular disease is multifactorial. Under certain circumstances, drugs with various mechanisms of action are combined. However, only a theoretical consideration of any combination of drugs having a different mode of action does not necessarily lead to combinations with predominant effects. Accordingly, there is a need for more effective combination therapy, which gives less harmful side effects.

In one aspect, the present invention relates to pharmaceutical combinations comprising valsartan or a pharmaceutically acceptable salt thereof and a neutral endopeptidase inhibitor (NEP) or a pharmaceutically effective salt thereof, optionally in the presence of a pharmaceutically acceptable carrier, and pharmaceutical compositions comprising them.

In another embodiment, the present invention relates to methods for treating cardiac and related renal conditions by administering a pharmaceutical composition comprising valsartan plus an NEP inhibitor, or relates to a pharmaceutical composition comprising valsartan or its pharmaceutically acceptable salts and a neutral endopeptidase inhibitor (NEP) or pharmaceutically effective thereof salt.

In another embodiment of the invention, the present invention relates to a pharmaceutical composition comprising valsartan or a pharmaceutically acceptable salt thereof and a neutral endopeptidase inhibitor (NEP) or a pharmaceutically effective salt and diuretic thereof, especially hydrochlorothiazide.

Valsartan is an antagonist of the AT 1 receptor, (S) -N- (1-carboxy-2-methylprop-1-yl) -N-pentanoyl-N- [2- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl ] an amine of the formula (I)

and disclosed in EP 0 443 983 A and US Pat. No. 5,399,578, the disclosures of which are incorporated by reference in their entirety, as if placed further in context.

The NEP inhibitor applicable in said combination means a compound of formula (II)

and its pharmaceutically acceptable salts,

Where

R ₂ means alkyl of 1-7 carbon atoms, trifluoromethyl, phenyl, substituted phenyl, - (CH ₂ ) _1-4 phenyl or - (CH ₂ ) _1-4 substituted phenyl;

R ₃ means hydrogen, alkyl of 1-7 carbon atoms, phenyl, substituted phenyl,

- (CH ₂ ) _1-4 phenyl; or - (CH ₂ ) _1-4 substituted phenyl;

R ₁ means hydroxy, alkoxy of 1-7 carbon atoms or amino;

n is a number 1-15; and

the term “substituted” phenyl refers to a substituent selected from (ness.) alkyl of 1-4 carbon atoms, (ness.) alkoxy of 1-4 carbon atoms, (ness.) alkylthio of 1-4 carbon atoms, hydroxy, chlorine bromine or fluorine.

Preferred selective neutral endopeptidase inhibitors of formula II include compounds

Where

R ₂ means benzyl;

R ₃ means hydrogen;

n is a number from 1 to 9; and

R ₁ means hydroxy.

An even more preferred selective neutral endopeptidase inhibitor of formula II is described in the literature as SQ 28603, which means a compound of formula II,

Where

R ₂ means benzyl;

R ₃ means hydrogen;

n is 1; and

R ₁ means hydroxy.

The preparation of selective neutral endopeptidase inhibitors of formula II, where R _{2 is} other than trifluoromethyl, is disclosed by Delaney et al. In US Pat. No. 4,722,810. The preparation of selective neutral endopeptidase inhibitors of formula II, where R ₂ is trifluoromethyl, is disclosed by Delaney and others in US Pat. No. 5,223,516.

NEP inhibitors within the scope of the present invention include the compounds disclosed in US Pat. No. 4,610,816, incorporated by reference, including in particular N- [N- [1 (S) -carboxyl-3-phenylpropyl] - (S) -phenylalanyl] - (S) -isoserine and NN - [((1S) -carboxy-2-phenyl) ethyl] - (S) -phenylalanyl] -β-alanine; compounds disclosed in US Pat. No. 4,929,641, especially N- [2 (S) -mercaptomethyl-3- (2-methylphenyl) propionyl] methionine; SQ 28603, (N- [2- (mercaptomethyl) -1-oxo-3-phenylpropyl] -β-alanine) disclosed in the application 84/0670; UK 69578 discloses cis-4 - [[[1- [2-carboxy-3- (2-methoxyethoxy) propyl] cyclopentyl] carbonyl] amino] cyclohexanecarboxylic acid and its active enantiomer (s); tiorphan and its enantiomers; retrotiorphan; phosphoramidone; and SQ 29072, (7 - [[2- (mercaptomethyl) -1-oxo-3-phenylpropyl] amino] heptanoic acid). Also useful are any depot forms of the above NEP inhibitors, for example, compounds in which one or more carboxyl groups are esterified.

NEP inhibitors within the scope of the present invention also include compounds disclosed in US Pat. No. 5,217,996, in particular N- (3-carboxy-1-oxopropyl) - (4S) -n-phenylphenylmethyl) -4-amino-2R-methylbutanoic acid ethyl ester and N- (3-carboxy-1-oxopropyl) - (4S) -n-phenylphenylmethyl-4-amino-2R-methylbutanoic acid or, in each case, his or her pharmaceutically acceptable salt; the compounds disclosed in EP 00342850, in particular (S) -cis-4- [1- [2- (5-indanyloxycarbonyl) -3- (2-methoxyethoxy) propyl] -1-cyclopentanecarboxamido] -1-cyclohexanecarboxylic acid; the compounds disclosed in GB 02218983, in particular 3- (1- [6-endohydroxymethylbicyclo [2.2.1] heptane-2-exocarbamoyl] cyclopentyl) -2- (2-methoxyethoxy) propanoic acid; the compounds disclosed in WO 92/14706, in particular N- (1- (3- (N-tert-butoxycarbonyl- (S) -prolylamino) -2 (S) -tert-butoxycarbonylpropyl) cyclopentanecarbonyl) -O- methyl ester benzyl- (S) -serine; compounds disclosed in patent EP 00343911; compounds disclosed in JP 06234754; the compounds disclosed in EP 00361365, in particular 4 - [[2- (mercaptomethyl) -1-oxo-3-phenylpropyl] amino] benzoic acid; the compounds disclosed in WO 90/09374, in particular 3- [1- (cis-4-carboxycarbonyl-cis-3-butylcyclohexyl-1-carbamoyl) cyclopentyl] -2S- (2-methoxyethoxymethyl) propanoic acid; the compounds disclosed in JP 07157459, in particular N - ((2S) -2- (4-biphenylmethyl) -4-carboxy-5-phenoxyvaleryl) glycine; compounds disclosed in WO 94/15908, in particular N- (1- (N-hydroxycarbamoylmethyl) -1-cyclopentanecarbonyl) -L-phenylalanine; compounds disclosed in US Pat. No. 5,273,990, in particular (S) - (2-biphenyl-4-yl) -1- (1H-tetrazol-5-yl) ethylamino) methylphosphonic acid; compounds disclosed in US patent 5294632, in particular (S) -5- (N- (2- (phosphonomethylamino) -3- (4-biphenyl) propionyl) -2-aminoethyl) tetrazole; compounds disclosed in US Pat. No. 5,250,522, in particular β-alanine, 3- [1,1'-biphenyl] -4-yl-N- [diphenoxyphosphinyl) methyl] -L-alanine; the compounds disclosed in patent EP 00636621, in particular N- (2-carboxy-4-thienyl) -3-mercapto-2-benzylpropanamide; the compounds disclosed in WO 93/09101, in particular 2- (2-mercaptomethyl-3-phenylpropionamido) thiazol-4-ylcarboxylic acid; the compounds disclosed in patent EP 00590442, in particular ((L) - (1 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) carbonyl) -2-phenylethyl) -L-phenylalanyl ) -β-alanine, N- [N - [(L) - [1 - [(2,2-dimethyl-1,3-dioxolan-4-yl) methoxy] carbonyl] -2-phenylethyl] -L-phenylalanyl ] - (R) -alanine, N- [N - [(L) -1-carboxy-2-phenylethyl] -L-phenylalanyl] - (R) - alanine, ethyl ester N- [2-acetylthiomethyl-3- ( 2-methylphenyl) propionyl] methionine, N- [2-mercaptomethyl-3- (2-methylphenyl) propionyl] methionine, N- [2 (S) -mercaptomethyl-3- (2-methylphenyl) propanoyl] - (S) - isoserine, N- (S) - [3-mercapto-2- (2-methylphenyl) propionyl] - (S) -2-methoxy- (R) -alanine, N- [1 - [[1 (S) -benzyloxycarbonyl -3-phenylpropyl] amino] cyclopentylcarbonyl] - (S) -isoserine, N- [1 - [[1 (S) -carbonyl-3-phenylpropyl] amino] cyclopentylcarbonyl] - (S) -isoserine, 1,1'- [dithiobis- [2 (S) - (2-methylbenzyl) -1-oxo-3,1-propanediyl]] - bis- (S) -isoserine, 1,1 '- [dithiobis- [2 (S) - ( 2-methylbenzyl) -1-oxo-3,1-propanediyl]] - bis- (S) -methionine, N- (3-phenyl-2- (mercaptomethyl) propionyl) - (S) -4- (methylmercapto) methionine N- [2-acetylthiomethyl-3-phenylpropionyl] -3-aminobenzoic acid, N- [2-mercaptomethyl-3-phenylpropionyl] -3-aminobenzoic acid, N- [1- (2-carboxy-4-phenylbutyl) cyclopentanecarbonyl ] - (S) -isoserine, ethyl N- [1- (acetylthiomethyl) cyclope tankarbonil] - (S) methionine, 3 (S) - [2- (acetylthiomethyl) -3-phenylpropionyl] amino-c-caprolactam; and the compounds disclosed in WO 93/10773, in particular N- (2-acetylthiomethyl-3- (2-methylphenyl) propionyl) methionine ethyl ester.

Diuretic means, for example, a thiazide derivative selected from the group consisting of chlortiazide, hydrochlorothiazide, methylclothiazide and chlortalidone. Most preferred is hydrochlorothiazide. The compounds to be combined may be present in the form of pharmaceutically acceptable salts. If these compounds contain, for example, at least one basic center, they can form acid addition salts. Corresponding acid addition salts can also be formed, having, if necessary, an additionally present basic center. Compounds containing at least one acid group (e.g. COOH) can also form salts with bases. In addition, corresponding internal salts can be formed if the compound contains, for example, both a carboxy group and an amino group.

For N- (3-carboxy-1-oxopropyl) - (4S) -n-phenylphenylmethyl) -4-amino-2R-methylbutanoic acid ethyl ester, preferred salts include the sodium salt disclosed in US Pat. No. 5,217,996, a salt with triethanolamine and a salt with tris (hydroxymethyl) aminomethane. The preparation of a salt with triethanolamine and a salt with tris (hydroxymethyl) aminomethane can be carried out as follows.

Triethanolamine: to the N- (3-carboxy-1-oxopropyl) - (4S) -n-phenylphenylmethyl) -4-amino-2R-methylbutanoic acid ethyl ester (349 mg, 0.848 mmol) were added 5 ml of ethyl ether and 0.113 ml ( 0.848 mmol) of triethanolamine in 1 ml of ethyl acetate. The solid was collected and dried, melting at 69-71 ° C.

Tris (hydroxymethyl) aminomethane: N- (3-carboxy-1-oxopropyl) - (4S) -n-phenylphenylmethyl) -4-amino-2R-methylbutanoic acid ethyl ester (3.2 g, 7.78 mmol) was added 32 ml of ethyl acetate and 940 mg (7.78 mmol) of tris (hydroxymethyl) aminomethane. The suspension was diluted with 45 ml of ethyl acetate and heated at reflux overnight (about 20 hours). The reaction mixture was cooled to 0 ° C, filtered, the solid was washed with ethyl acetate and dried, melting at 114-115 ° C.

N- (3-carboxy-1-oxopropyl) - (4S) -n-phenylphenylmethyl) -4-amino-2R-methylbutanoic acid ethyl ester salts with triethanolamine and tris (hydroxymethyl) aminomethane are new and can be used as NEP inhibitors . Another embodiment of the present invention are said new salts, their use as NEP inhibitors, especially for the prevention and treatment of conditions and diseases associated with NEP inhibition, a pharmaceutical composition comprising these salts and their combinations with valsartan, in particular for the treatment of conditions and diseases as disclosed for the combinations of the present invention above and below.

It was unexpectedly found that the combination of valsartan and an NEP inhibitor gives a greater therapeutic effect than the administration of valsartan, ACE inhibitors or NEP inhibitors separately, and contributes to the formation of angioedema less than that observed with the introduction of a single vasopeptidase inhibitor. Higher efficacy can also be justified as an increased duration of action. The duration of action can be controlled either as the time of return to the baseline before the next dose, or as the area under the curve (AUC) and expressed as the result of a change in blood pressure in mm of mercury (change in mm of mercury) and duration of effect (minutes, hours or days).

Further advantages are that lower doses of the individual preparations to be combined according to the present invention can be used in order to reduce the dosage, for example, it is necessary that in most cases the doses are not only lower, but also are used less often, or can be used to reduce the frequency of side effects. The combined administration of valsartan or its pharmaceutically acceptable salt and an NEP inhibitor or its pharmaceutically acceptable salt leads to a significant response in a larger percentage of patients treated, i.e. leads to a higher response rate of the responding organism, regardless of the underlying etiology of the condition. This is in accordance with the desires and needs of the patients to be treated.

It can be shown that combination therapy with valsartan and an NEP inhibitor leads to a more effective antihypertensive therapy (for malignant, primary arterial, vasorenal, diabetic, isolated systolic or other symptomatic type of hypertension) through improved efficacy as well as a higher response rate of the responding organism. The combination is also useful in the treatment or prevention of heart failure, such as (acute or chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, or atrial flutter. In addition, valsartan and an NEP inhibitor have been shown to be useful in treating and preventing myocardial infarction and its consequences. The combination of valsartan plus an NEP inhibitor is also useful in the treatment of atherosclerosis, angina pectoris (persistent or unstable) and renal failure (diabetic and non-diabetic). Moreover, combination therapy using valsartan and an NEP inhibitor can improve endothelial dysfunction, thereby providing an advantage in diseases in which normal endothelial function is impaired, such as heart failure, angina pectoris and diabetes. In addition, the combination of the present invention can be used to treat and prevent secondary aldoster, primary and secondary pulmonary hypertension, conditions of renal failure such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria in primary renal disease and also renal vascular hypertension, diabetic retinopathy, management of other vascular disorders such as migraine, peripheral vascular disease, Raynaud's disease, luminal hyperplasia AI, dysfunction of consciousness (such as Alzheimer's disease), glaucoma and paralysis.

The structure of active agents identified by generic or trade names, or code numbers, can be obtained from the current edition of The Merck Index Standard Guide or from databases such as Life Cycle Patents International (such as IMS World Publications). Their respective contents are hereby incorporated by reference. Any specialist in this field is fully capable of identifying active agents and, based on these links, is thus able to obtain and study pharmaceutical indications and properties on standard experimental models both in vitro and in vivo.

The subject of NEP inhibitors, referred, for example, to US patents, EP, GB, JP or WO applications, is hereby incorporated by reference, especially the corresponding NEP inhibitors and their pharmaceutically acceptable salts and pharmaceutical compositions as set forth in the claims or disclosed in the working examples.

The person skilled in the art is fully capable of selecting a relevant experimental model to prove the effectiveness of the combination of the present invention for therapeutic indications indicated above and below.

Representative studies were performed with a combination of valsartan and N- (3-carboxy-1-oxopropyl) - (4S) -n-phenylphenylmethyl) -4-amino-2R-methylbutanoic acid ethyl ester, for example, using the following methodology.

The effectiveness of the drug was evaluated in various animal models, including a rat treated with deoxycorticosterone acetate and salt (DOGA salt), and a rat with spontaneous hypertension (SHR) or maintained on a normal salt diet, or with a salt load (4-8% salt in rat food or 1% sodium chloride as drinking water).

Experimental Model DOCA-salt uses either an acute or chronic study protocol. The acute research technique involves evaluating the effects of various test substances over a six-hour experimental period using rats with permanently located femoral arterial and venous catheters. The acute study technique evaluates the test substances by their ability to lower blood pressure during the established phase of DOCA-salt hypertension. In contrast, a chronic study technique evaluates the ability of a test substance to prevent or delay an increase in blood pressure during the evolutionary phase of DOCA-salt hypertension. Therefore, blood pressure in the method of chronic research will be monitored by means of a radio sensor. A radio sensor is surgically implanted in the abdominal rat aorta before treatment with DOCA salt and, thus, before induction of hypertension. Blood pressure is constantly monitored for periods of up to 6 weeks (approximately one week before the administration of DOCA salt and for 5 weeks after).

Rats were anesthetized with 2-3% isoflurane in inhaled oxygen, then using sodium amital (amobarbital) at a dose of 100 mg / kg intraperitoneally. The level of anesthesia was evaluated using the characteristics of calm rhythmic breathing.

Acute research technique

Rats underwent unilateral nephrectomy during DOCA implantation. The wool was fastened with clamps on the left side and the back of the neck and treated with sterile swabs with alcohol and povidone / iodine. During surgery, rats were placed on a warming pad to maintain the temperature at 37 ° C.

A 20 mm incision was made through the skin and the muscle beneath it to highlight the left kidney. The kidney was freed from the surrounding tissue, temporarily removed to the surface of the body, and two ligatures (3-0 silk) were firmly fixed around the renal artery and veins located proximal to their connection with the aorta. Then the renal artery and vein were cut and the kidney was removed. Muscle and skin wounds were closed with a surgical suture (4-0 silk) and stainless steel wound clips, respectively. At the same time, a 15 mm incision was made on the back of the neck and a granule was implanted subcutaneously to release the active ingredient for 3 weeks (Innovative Research of America, Florida) containing deoxycorticosterone acetate (100 mg / kg). The wound was then closed with stainless steel clamps, and both wounds were treated with povidone / iodine; rats received a post-surgical intramuscular injection of penicillin G (100,000 units) against the background of procaine and buprenorphine (0.05-0.1 mg / kg) was subcutaneously administered. Rats were immediately given drinking water containing 1% sodium chloride and 0.2% potassium chloride; this treatment lasted at least 3 weeks, during which time the animals became hypertensive and available for experimentation.

Forty-eight hours before the experiments, the animals were anesthetized with isoflurane and catheters were implanted in the femoral artery and vein to measure pressure, collect blood and administer the test compounds. Rats were allowed to recover for 48 hours when they were tied in a cage made of organic glass, which also served as an experimental chamber.

Chronic research technique

This technique is the same as described above, except that the rats were implanted with a radio sensor 7-10 days before a unilateral nephrectomy and the start of DOCA and salt treatment. In addition, the rats did not undergo surgery to install femoral arterial and venous catheters. The radio sensors were implanted as described by M.K. Bazil, C. Krulan and R. L. Webb. Telemetric monitoring of cardiovascular parameters in conscious spontaneously hypertensive rats. J. Cardiovasc. Pharmacol. 22: 897-905, 1993.

Then the protocols were entered into a computer to measure blood pressure, heart rate, etc. at predetermined time points. Baseline data was collected at various time points and over various time intervals. For example, a baseline of pre-dose values usually consists of a combination of data and averaging over the next 3 24-hour time periods before drug administration.

Blood pressure, heart rate and activity were determined at various pre-selected time points before, during and after drug administration. All measurements were carried out on unlimited and intact animals. The longest study time, determined by a combination of several life criteria, could be nine months long. For studies of this duration, rats were given orally (1-3 ml / kg excipient) no more than twice a day daily, or the drug was administered in drinking water or mixed with food. For studies with shorter duration, i.e. up to 8 weeks, drugs were administered using subcutaneously implanted osmotic mini-pumps. Osmotic mini pumps were selected based on the speed and time of drug delivery. Doses of valsartan ranged from 1 to 10 mg / kg / day, and the doses of N- (3-carboxy-1-oxopropyl) - (4S) -n-phenylphenylmethyl) -4-amino-2R-methylbutanoic acid ethyl ester varied in ranges from 10 to 50 mg / kg / day.

In addition, spontaneous hypertension (SHR) rats were used to study the effects of valsartan in combination with N- (3-carboxy-1-oxopropyl) - (4S) -n-phenylphenylmethyl) -4-amino-2R-methylbutanoic acid ethyl ester. Hypertensive background SHR was modified either by chronic salt loading in an attempt to suppress the renin-angiotensin (RAS) system, or by chronic salt depletion to activate RAS in spontaneous hypertension rats. These manipulations will be carried out in order to more broadly evaluate the effectiveness of various test substances. The experiments were performed on rats with spontaneous hypertension (SHR), supplied by Taconic Farms, Germantown, New York (Tac: N (SHR) fBR). A radio telemetry device (Data Sciences International, Inc., St. Paul, Minnesota) was implanted into the lower abdominal aorta in all of the test animals between the ages of 14 and 16 weeks. All SHRs were allowed to recover from the surgical implantation procedure for at least 2 weeks before the start of the experiments. Cardiovascular parameters were continuously monitored using a radio sensor and transmitted to a radio receiver, where the digitalized signal was then captured and stored using a computerized data storage system. Blood pressure (mean arterial, systolic and diastolic blood pressure) and heart rate were monitored in conscious, freely moving and intact SHRs in the living cells. Arterial blood pressure and heart rate were measured every 10 min for 10 s and recorded. The data reported for each rat are average values averaged over a 24-hour period and are composed of 144 ten-minute measurements collected each day. The baseline values for blood pressure and heart rate consist of the average of three consecutive 24-hour measurements obtained before starting treatment with the drug. All rats were housed separately in a room with controlled temperature and humidity and kept in a 12-hour light-dark cycle.

In addition to cardiovascular parameters, body rats were also recorded in all rats. The drugs were administered in drinking water orally through a gastric tube or using osmotic mini-pumps, as described above. When introduced into drinking water, water consumption was measured five times a week. The doses of valsartan and N- (3-carboxy-1-oxopropyl) - (4S) -n-phenylphenylmethyl) -4-amino-2R-methylbutanoic acid ethyl ester were then calculated based on the water consumption of each rat, the drug concentration in drinking water and individual body masses. All drug solutions were prepared fresh every 3-4 days. In combination, lower doses of each drug are used, and accordingly, valsartan is administered in the range of 1-30 mg / kg / day and N- (3-carboxy-1-oxopropyl) - (4S) -n-phenylphenylmethyl) -4-amino ethyl ester -2R-methylbutanoic acid in doses below 50 mg / kg / day. However, in cases when the response rate of the body increases during combination therapy, the doses are identical to those used in monotherapy.

When drugs are administered orally with a gastric tube, the dose of valsartan varies from 1 to 50 mg / kg / day, and the ethyl ester of N- (3-carboxy-1-oxopropyl) - (4S) -n-phenylphenylmethyl) -4- amino-2R-methylbutanoic acid does not exceed 100 mg / kg / day.

At the end of the chronic SHR studies and the DOCA-treated rats, the rats were anesthetized and their heart removed quickly. After separation and removal of the atrial ears, the left ventricle and left plus right ventricle (in total) were weighed and recorded. The left ventricular and total ventricular mass were then reduced to body weight and described. All values reported for blood pressure and heart mass represent a group mean ± standard deviation.

Vascular function and structure were evaluated after treatment to determine the beneficial effects of the combination. SHR was investigated in accordance with the methods described by Intengan H. D., Thibault G., Li J. S., Schiffrin E. L., Circulation 1999, 100 (22): 2267-2275. Similarly, the methodology for assessing vascular function in rats treated with DOCA salt is described by Intengan H. D., Park J. B., Schiffrin, E. L., Hypertension, 1999, 34 (4, part 2): 907-913.

Available results indicate an unexpected therapeutic effect of the combination of the invention.

In one aspect, an object of the present invention is to provide a pharmaceutical combination composition, for example, for treating or preventing a condition or disease selected from the group consisting of hypertension, heart failure, such as (acute and chronic) congestive heart failure, left ventricular dysfunction, and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, harmful to river health vascular structures, myocardial infarction and its consequences, atherosclerosis, angina pectoris (unstable or persistent), renal failure (diabetic and non-diabetic), heart failure, angina pectoris, diabetes, secondary aldoster, primary and secondary pulmonary hypertension, conditions of renal failure such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria in primary renal disease and also renal vascular hypertension, diabetic retinopathy, in other vascular disorders, such as migraine, peripheral vascular disease, Raynaud’s disease, luminal hyperplasia, consciousness dysfunction (such as Alzheimer's disease), glaucoma and paralysis, a composition that includes (i) an AT-1 receptor antagonist valsartan or its pharmaceutically acceptable a salt and (ii) an NEP inhibitor or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. An additional active ingredient may be a diuretic, especially hydrochlorothiazide.

In this composition, components (i) and (ii) can be prepared and administered together, one after the other, or separately in one combined unit dosage form or in two separate unit dosage forms. The unit dosage form may also be a given combination.

An additional aspect of the present invention is a method of treating or preventing a condition or disease selected from the group consisting of hypertension, heart failure, such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias , atrial fibrillation, atrial flutter, unhealthy vascular reconstruction, myocardial infarction and its consequences, at rosclerosis, angina pectoris (unstable or persistent), renal failure (diabetic and non-diabetic), heart failure, angina pectoris, diabetes, secondary aldoster, primary and secondary pulmonary hypertension, conditions of renal failure such as diabetic nephropathy, glomerulonephritis, scleroderma proteinuria in primary renal disease and also renal vascular hypertension, diabetic retinopathy, management of other vascular disorders such as migraine, disease peripheral vascular disease, Raynaud’s disease, luminal hyperplasia, consciousness dysfunction (such as Alzheimer's disease), glaucoma and paralysis, including the administration of a therapeutically effective amount of a combination of (i) an AT-1 receptor antagonist valsartan or a pharmaceutically acceptable salt thereof and (ii) an NEP inhibitor or a pharmaceutically acceptable salt and pharmaceutically acceptable carrier thereof to a mammal in need of such treatment.

A therapeutically effective amount of each component of the combination of the present invention can be administered simultaneously or sequentially and in any order.

The corresponding active ingredient or a pharmaceutically acceptable salt thereof may also be used in the form of a hydrate or may include other solvents used for crystallization.

The pharmaceutical compositions of the invention can be prepared in a manner known per se and suitable for enteral, such as oral or rectal, and parenteral administration to mammals (warm-blooded mammals), encompassing humans, comprising a therapeutically effective amount of a pharmacologically active compound, alone or in combination with one or more pharmaceutically acceptable carriers, especially suitable for enteral or parenteral use. Typical oral forms include tablets, capsules, syrups, elixirs and suspensions. Typical injectable forms include solutions and suspensions.

Examples of typical pharmaceutically acceptable carriers for use in the combinations described above are: sugars such as lactose, sucrose, mannitol and sorbitol; starches such as corn starch, tapioca starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose, calcium phosphates such as dicalcium phosphate and tricalcium phosphate; sodium sulfate; calcium sulfate; polyvinylpyrrolidone; polyvinyl alcohol; stearic acid; alkaline earth metal stearates such as magnesium stearate and calcium stearate; stearic acid; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil; nonionic, cationic and anionic surfactants; ethylene glycol polymers; β-cyclodextrin; fatty alcohols; and hydrolyzed cereal solids, as well as other non-toxic compatible excipients, binders, disintegrants, buffers, preservatives, antioxidants, lubricants, flavoring agents, and the like, commonly used in pharmaceutical compositions.

The invention also relates to combining individual pharmaceutical compositions in a kit. That is, a kit combining two separate units: the valsartan pharmaceutical composition and the NEP inhibitor pharmaceutical composition. The kit is especially useful when two separate components must be administered in different dosage forms (for example, the parenteral form of valsartan and the oral form of an NEP inhibitor) or administered at different dosage intervals.

These pharmaceutical preparations are preparations for enteral, such as oral and also rectal, or parenteral administration in warm-blooded formulations, comprising a pharmacologically active compound, or alone, or together with conventional pharmaceutical excipients. For example, pharmaceutical preparations consist of from about 0.1% to 90%, preferably from about 1% to about 80% of the active compounds.

Pharmaceutical preparations for enteral or parenteral administration are, for example, in unit dosage forms, such as coated tablets, tablets, capsules or suppositories, and also ampoules. They are obtained by a method that is essentially known, for example, using conventional techniques of mixing, granulation, coating, solubilization or lyophilization. So, pharmaceutical preparations for oral administration can be obtained by combining the active compounds with solid excipients, if necessary, granulating the mixture that was obtained, and if necessary or necessary, after adding the appropriate excipients, processing the mixture or granulate into tablets or tablet cores coated.

The dose of the active compound may depend on various factors, such as the type of administration, the type of warm-blooded, age and / or individual condition.

Preferred doses of the active ingredients for the pharmaceutical combination of the present invention are therapeutically effective doses, especially those that are commercially available.

Typically, in the case of oral administration, an approximate daily dose of from about 1 mg to about 360 mg should be established, for example, for a patient weighing about 75 kg.

Valsartan is supplied in the form of an appropriate unit dosage form, for example, a capsule or tablet, containing a therapeutically effective amount, for example, from about 20 to about 320 mg of valsartan, which can be used by patients. The use of the active ingredient can occur up to three times a day, starting, for example, with a daily dose of 20 mg or 40 mg of valsartan, increasing from 80 mg daily and then to 160 mg daily to 320 mg daily. Preferably, in patients with heart failure, valsartan is used once a day or twice a day at a dose of 80 mg or 160 mg each, respectively. Appropriate doses may be taken, for example, in the morning, at noon or in the evening. Preferred for heart failure is the introduction of four or two times a day.

In the case of NEP inhibitors, preferred unit dosage forms are, for example, tablets or capsules comprising, for example, from about 20 mg to about 800 mg, preferably from about 50 mg to about 700 mg, even more preferably from about 100 mg to about 600 mg and even more preferably from about 100 mg to about 300 mg, administered once a day.

In the case of diuretics, preferred unit dosage forms are, for example, tablets or capsules comprising, for example, from about 5 mg to about 50 mg, preferably from about 6.25 mg to about 25 mg. A daily dose of 6.25 mg, 12.5 mg or 25 mg of hydrochlorothiazide is preferably administered once a day.

The above doses encompass a therapeutically effective amount of the active ingredients of the present invention.

The following examples illustrate the invention described above; however, this does not in any way imply a limitation on the scope of the invention.

Formulation Example 1

Coated tablets

Components Composition per unit (mg) Standards Granulation Valsartan (active ingredient) 80.00 Microcrystalline cellulose / Avitel pH 102 54.00 NF, Pharmacopoeia of Europe Crospovidone 20.00 NF, Pharmacopoeia of Europe Colloidal Anhydrous SiO ₂ / Colloidal SiO ₂ / Aerosil 200 0.75 Pharmacopoeia of Europe / NF Magnesium stearate 2,5 NF, Pharmacopoeia of Europe Mixing Colloidal Anhydrous SiO ₂ / Colloidal SiO ₂ / Aerosil 200 0.75 Pharmacopoeia of Europe / NF Magnesium stearate 2.00 NF, Pharmacopoeia of Europe Coating Purified water* - DIOLAC pale red 00F34899 7.00 Total tablet weight 167.00 * Deleted during processing

A coated tablet is made, for example, as follows.

A mixture of valsartan, microcrystalline cellulose, crospovidone, a portion of colloidal anhydrous silica / colloidal silica / Aerosil 200, silica and magnesium stearate is pre-mixed in a diffusion mixer and then sieved through a screening grinder. The resulting mixture is again pre-mixed in a diffusion mixer, compacted in a roller press and then sieved through a sorting grinder. The residue of colloidal anhydrous silica / colloidal silica / Aerosil 200 is added to the resulting mixture, and the final mixture is treated in a diffusion mixer. The whole mixture is compressed in a rotary tabletting machine and the tablets are coated using pale red diolac in a perforated tank.

Formulation Example 2

Coated tablets

Components Composition per unit (mg) Standards Granulation Valsartan (active ingredient) 160.00 Microcrystalline cellulose / Avicel PH 102 108.00 NF, Pharmacopoeia of Europe Crospovidone 40.00 NF, Pharmacopoeia of Europe Colloidal Anhydrous SiO ₂ / Colloidal SiO ₂ / Aerosil 200 1,5 Pharmacopoeia of Europe / NF Magnesium stearate 5,0 NF, Pharmacopoeia of Europe Mixing Colloidal Anhydrous SiO ₂ / Colloidal SiO ₂ / Aerosil 200 1,5 Pharmacopoeia of Europe / NF Magnesium stearate 4.00 NF, Pharmacopoeia of Europe Coating Opadri® Pale Brown OOF33172 7.00 Total tablet weight 330.00

A coated tablet is made, for example, as described in Example 1 of the preparation of the dosage form.

Formulation Example 3

Coated tablets

Components Composition per unit (mg) Standards Core: internal phase Valsartan (active ingredient) 40.00 Silicon dioxide, colloidal anhydrous (colloidal silicon dioxide) (gliding agent) 1.00 Pharmacopoeia of Europe, USP / NF Magnesium Stearate (Lubricant) 2.00 USP / NF Crospovidone (disintegrator) 20.00 Pharmacopoeia of Europe Microcrystalline cellulose (binding agent) 124.00 USP / NF External phase Silicon dioxide, colloidal anhydrous (colloidal silicon dioxide) (gliding agent) 1.00 Pharmacopoeia of Europe, USA / NF Magnesium Stearate (Lubricant) 2.00 USP / NF Coating Opadri® Brown OOF 16711 * 9.40 Purified water** - Total tablet weight 199.44 * The Opadri® Brown OOF 16711 coloring agent composition is shown in the table below.
** Deleted during processing.

Opadri® Composition

Ingredient Approximate% of composition Black iron oxide (C.I. No. 77499, E 172) 0.50 Brown Iron Oxide (C.I. No. 77499, E 172) 0.50 Iron oxide red (C.I. No. 77491, E 172) 0.50 Iron Oxide Yellow (C.I. No. 77492, E 172) 0.50 Macrogolum (Pharmacopoeia of Europe) 4.00 Titanium Dioxide (C.I. No. 77891, E 171) 14.00 Hypromellose (Pharmacopoeia of Europe) 80.00

A coated tablet is made, for example, as described in Example 1 of the preparation of the dosage form.

Formulation Example 4

Capsules

Components Composition per unit (mg) Valsartan (active ingredient) 80.00 Microcrystalline cellulose 25.10 Crospovidone 13.00 Povidone 12.50 Magnesium stearate 1.30 Sodium Lauryl Sulfate 0.60 Shell Iron oxide red (C.I. No. 77491, EC No. E 172) 0.123 Yellow Iron Oxide (C.I. No. 77492, EC No. El 72) 0.123 Black iron oxide (C.I. No. 77499, EC No. E 172) 0.245 Titanium dioxide 1,540 Gelatin 74,969 Total tablet weight 209.50

A tablet was made, for example, as follows.

Granulation / drying

Valsartan and microcrystalline cellulose were spray granulated in a fluidized bed granulator with a granulating solution consisting of povidone and sodium lauryl sulfate dissolved in purified water. The obtained granulate was dried in a fluidized bed dryer.

Grinding / mixing

The dried granulate was crushed together with crospovidone and magnesium stearate. The mass was then mixed in a screw-type conical mixer for about 10 minutes.

Encapsulation

Empty hard gelatin capsules were filled with mixed bulk granules under conditions of controlled temperature and humidity. The filled capsules were free from dust, visually inspected, the mass was checked and isolated until then with the help of the Quality Assurance Department.

Formulation Example 5

Capsules

Components Composition per unit (mg) Valsartan (active ingredient) 160.00 Microcrystalline cellulose 50,20 Crospovidone 26.00 Povidone 25 Magnesium stearate 2.60 Sodium Lauryl Sulfate 1.20 Shell Iron oxide red (C.I. No. 77491, EC No. E 172) 0.123 Iron Oxide Yellow (C.I. No. 77492, EC No.El 72) 0.123 Black iron oxide (C.I. No. 77499, EC No. E 172) 0.245 Titanium dioxide 1,540 Gelatin 74,969 Total tablet weight 342.00

A dosage form was prepared, for example, as described in Example 4 for the preparation of a dosage form.

Formulation Example 6

Hard gelatin capsule

Components Composition per unit (mg) Valsartan (active ingredient) 80.00 Sodium Lauryl Sulfate 0.60 Magnesium stearate 1.30 Povidone 12.50 Crospovidone 13.00 Microcrystalline cellulose 21.10 Total tablet weight 130.00

Formulation Example 7

A hard gelatin capsule containing, as an active ingredient, for example, (S) -N- (1-carboxy-2-methylprop-1-yl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl ) biphenyl-4-ylmethyl] amine, can be developed, for example, as follows.

Composition:

(1) valsartan 80.0 mg (2) microcrystalline cellulose 110.0 mg (3) polyvidone K-30 45.2 mg (4) sodium lauryl sulfate 1.2 mg (5) crospovidone 26.0 mg (6) magnesium stearate 2.6 mg

Components (1) and (2) were granulated with a solution of components (3) and (4) in water. Components (5) and (6) were added to the dry granulate and the mixture was filled in size 1 hard gelatin capsules.

All publications and patents mentioned in the context, in their entirety, are incorporated by reference, as if they were set forth in full in the context.

Claims (5)

1. A pharmaceutical combination comprising (i) an AT-1 antagonist valsartan or a pharmaceutically acceptable salt thereof in a unit daily dose of from about 20 mg to about 320 mg, and (ii) an NEP inhibitor which is N- (3-carboxy-1-oxopropyl) - (4S) -n-phenylphenylmethyl) -4-amino-2R-methylbutanoic acid ethyl ester or N- (3-carboxy-1-oxopropyl) ) - (4S) -n-phenylphenylmethyl) -4-amino-2R-methylbutanoic acid or their pharmaceutically acceptable salt in a single daily dose of from about 20 mg to about 800 mg and a pharmaceutically acceptable carrier for treating or preventing a condition or disease selected from the group consisting of hypertension, heart failure, such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atria, unhealthy vascular reconstruction, myocardial infarction and its consequences, atherosclerosis, angina pectoris (unstable or steady), renal insufficiency (diabetic and non-diabetic), heart failure, angina pectoris, diabetes, secondary aldoster, primary and secondary pulmonary hypertension, conditions of renal failure, such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria in primary renal renal disease , diabetic retinopathy, the ability to cope with other vascular disorders, such as migraine, peripheral vascular disease, Raynaud’s disease, etc. Swetnam hyperplasia consciousness dysfunction (such as Alzheimer's), glaucoma and stroke. 2. The pharmaceutical combination according to claim 1, comprising an NEP inhibitor comprising N- (3-carboxy-1-oxopropyl) - (4S) -n-phenylphenylmethyl) -4-amino-2R-methylbutanoic acid ethyl ester or its salt with triethanolamine or tris (hydroxymethyl) aminomethane. 3. The pharmaceutical combination according to claim 1, additionally containing a diuretic. 4. A kit for treating or preventing a condition or disease selected from the group consisting of hypertension, heart failure, such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, fibrillation atrial flutter, atrial flutter, unhealthy vascular reconstruction, myocardial infarction and its consequences, atherosclerosis, angina pectoris (unstable or steady), renal failure (diabetic and non-diabetic), heart failure, angina pectoris, diabetes, secondary aldoster, primary and secondary pulmonary hypertension, conditions of renal failure such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, and primary proteinuria in primary hypertension, diabetic retinopathy, the ability to cope with other vascular disorders, such as migraine, peripheral vascular disease, disease P doppler, luminal hyperplasia, consciousness dysfunction (such as Alzheimer's disease), glaucoma and paralysis, containing in one package in separate containers a pharmaceutical combination containing in one container a pharmaceutical composition comprising N- (3-carboxy-1-oxopropyl ethyl ether) - (4S) -n-phenylphenylmethyl) -4-amino-2R-methylbutanoic acid or N- (3-carboxy-1-oxopropyl) - (4S) -n-phenylphenylmethyl) -4-amino-2R-methylbutanoic acid or their a pharmaceutically acceptable salt; and in a second container, a pharmaceutical composition comprising valsartan. 5. A method of treating or preventing a condition or disease selected from the group consisting of hypertension, heart failure, such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation , atrial flutter, unhealthy vascular reconstruction, myocardial infarction and its consequences, atherosclerosis, angina pectoris (unstable or stable), soil heart failure (diabetic and non-diabetic), heart failure, angina pectoris, diabetes, secondary aldoster, primary and secondary pulmonary hypertension, conditions of renal failure, such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, and proteinuria in primary renal disease hypertension, diabetic retinopathy, the ability to cope with other vascular disorders, such as migraine, peripheral vascular disease, Rhine disease o, luminal hyperplasia, consciousness dysfunction (such as Alzheimer's disease), glaucoma and paralysis, comprising administering a therapeutically effective amount of a combination (i) of the AT-1 receptor antagonist valsartan or its pharmaceutically acceptable salt in a single daily dose from about 20 mg to about 320 mg and (ii) N- (3-carboxy-1-oxopropyl) - (4S) -n-phenylphenylmethyl) -4-amino-2R-methylbutanoic acid ethyl ester or N- (3-carboxy-1-oxopropyl) - ( 4S) -n-phenylphenylmethyl) -4-amino-2R-methylbutanoic acid or a pharmaceutically acceptable thereof salt in a single daily dose of from about 20 mg to about 800 mg.